The feline major histocompatibility complex (MHC) has been studied for an approach to comparative gene organization of this multigene cluster in mammals. In a large scale sequencing project of the feline MHC, we have constructed sequence contigs consisting of 1,170,994 base pairs (bps) in feline MHC class I and class II regions. A total of 57 coding genes were found in these regions, including 13 class I genes, 14 class II genes, 2 class III genes, 14 LINE 1 homologues and 14 new genes. Sequences of 448,147 bps (38.3 %) consist of repeat sequences, including 455 SINE elements, 402 LINE elements, 92 LTR elements, and 274 simple repeats. We have completed sequencing of 464,765 bps including 124,139 bps in DP to DM class II region -DPB, DPA, DNA, RING 3, DMA and DMB genes-, 60,089 bps in TAP class II region,-TAP1, LMP7, TAP2, DOB genes-, 97,500 bps in DRA and DRB regions, -4 DRB and one DRA gene-, and 130,654 bps in class I region, consisting of BAT1 (RNA helicase gene) and three class I genes. Comparisons between these sequences and human HLA sequences revealed that; (i) Sequences from DNA to DMB genes (approximately 100 kb) and from TAP1 to DOB genes (approximately 60 kb) maintain consecutive stretches of high similarity between human and feline MHCs; (ii) A sequence of an approximately 50 kb region including DPB and DPA genes are highly diverged between human and feline MHCs by large scale dot plot analysis. Feline DPB and DPA genes appear to encode functional peptides, suggesting possible selections for sequence divergence; (iii) The feline DR region consists of at least 4 DRB genes and one DRA gene in the order DRB1, DRA, DRB2 (pseudogene), DRB3, and DRB4. Phylogenetic analyses of the polymorphic exon 2 region of these DRB genes, plus previously reported 61 DRB exon 2 sequences showed that these DRB1, DRB3, and DRB4 genes encode exon2 sequences that belong to DRB*5, DRB*2, and DRB*1 lineages, respectively; and (iv) A unit of approximately 15 kb sequence consisting of homologues of HERV14, BAT1, class I genes is amplified at least three times in the feline MHC class I region. - Class I and Class II genes, Evolution, Felids, Major Histocompatibility Complex, - Neither Human Subjects nor Human Tissues